Agouti-related protein (AGRP) and agouti (ASP) are the only two naturally occurring antagonists of G-protein coupled receptors (GPCRs) identified to date, and when over expressed in mice, result in an obese phenotype. Obesity (body mass index >25) afflicts millions of people in the United States and other countries, and is a major risk factor for heart disease, type II diabetes mellitus, stroke and hypertension. In industrialized countries, the problem of obesity is compounded by overeating, a high fat content diet, and a lack of exercise. The last few years have seen the characterization of over 30 pathways that have been identified to participate in and regulate feeding behavior and energy homeostasis. The melanocortin pathway includes the melanocortin agonists, derived from the preprohormone proopiomelanocortin (POMC) gene transcript, the five melanocortin receptors identified to date (MC1R-MC5R), and the only 2 naturally occurring antagonists of GPCRs, agouti (ASP) and agouti-related protein (AGRP). Four melanocortin genetic factors expressed in neurons (POMC, AGRP, MC3R, and MC4R) have been identified as being involved in energy homeostasis. AGRP is a competitive antagonist at the MC3R and MC4R as well as an inverse agonist at the MC4R. An AGRP polymorphism has been identified in humans diagnosed with anorexia nervosa, linking AGRP with a human physiological disease state. These data support the hypothesis that AGRP is involved in the regulation of melanocortin receptor mediated neuropharmacology. The aims of the current application are to a) design and synthesize ligands with increased receptor subtype potency and/or selectivity, b) identify putative ligand-receptor interactions for the rational design of potential therapeutic molecules, and c) study selected molecules in mice. To achieve these objectives, we will use peptide design, combinatorial libraries, and GPCR mutagenesis strategies. Additionally, biophysical techniques [2D 1H NMR and computer assisted molecular modeling (CAMM)] will also be used and selected compounds will be administered into the brain and periphery of wild type and MC4R knock out mice to study physiological changes. PUBLIC HEALTH RELEVANCE: Obesity is a complex disease and is a risk factor for several other associated diseases. The melanocortin pathway has been identified in mice and humans, to regulate obesity. This research project proposes to generate knowledge for the rational design of molecules as potential therapeutic agents to prevent or treat the diseases associated with over or under eating.